At New York University, psilocybin trips take place in a treatment room carefully decorated to look more like a cozy den than a hospital suite. The effect almost works, but not entirely, for the stainless steel and plastic fittings of modern medicine peek through the domestic scrim here and there, chilly reminders that the room you are tripping in is still in the belly of a big city hospital complex.

Against one wall is a comfortable couch long enough for a patient to stretch out on during a session. An abstract painting—or is it a cubist landscape?—hangs on the opposite wall, and on the bookshelves large-format books about art and mythology share space with native craft items and spiritual knickknacks—a large glazed ceramic mushroom, a Buddha, a crystal. This could be the apartment of a well-traveled shrink of a certain age, one with an interest in Eastern religions and the art of what used to be called primitive cultures. Yet the illusion crumbles as soon as you lift your gaze to the ceiling, where the tracks that would ordinarily support the curtains dividing one hospital bed from another traverse the white acoustic tiles. And then there is the supersized bathroom, ablaze with fluorescent light and outfitted with the requisite grab bars and pedals.

It was here in this room that I first heard the story of Patrick Mettes, a volunteer in NYU’s psilocybin cancer trial who, in the course of a turbulent six-hour psilocybin journey on the couch where I now sat, had a life-changing—or perhaps I should say death-changing—experience. I had come to interview Tony Bossis, the palliative care psychologist who guided Mettes that day, and his colleague Stephen Ross, the Bellevue psychiatrist who directed the trial, which sought to determine whether a single high dose of psilocybin could alleviate the anxiety and depression that often follow a life-threatening cancer diagnosis.

While Bossis, hirsute and bearish, looks the part of a 50-something Manhattan shrink with an interest in alternative therapies, Ross, who is in his forties, comes across as more of a straight arrow; neatly trimmed in a suit and tie, he could pass for a Wall Street banker. A bookish teenager growing up in LA, Ross says he had no personal experience of psychedelics and knew next to nothing about them before a colleague happened to mention that LSD had been used successfully to treat alcoholics in the 1950s and 1960s. This being his psychiatric specialty, Ross did some research and was astonished to discover a “completely buried body of knowledge.” By the 1990s, when he began his residency in psychiatry at Columbia and the New York State Psychiatric Institute, the history of psychedelic therapy had been erased from the field, never to be mentioned.

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The trial at NYU, along with a sister study conducted in Roland Griffiths’s lab at Johns Hopkins, represents one of a handful of efforts to pick up the thread of inquiry that got dropped in the 1970s when sanctioned psychedelic therapy ended. While the NYU and Hopkins trials are assessing the potential of psychedelics to help the dying, other trials now under way are exploring the possibility that psychedelics (usually psilocybin rather than LSD, because, as Ross explained, it “carries none of the political baggage of those three letters”) could be used to lift depression and break addictions—to alcohol, cocaine, and tobacco.

None of this work is exactly new: to delve into the history of clinical research with psychedelics is to realize that most of this ground has already been tilled. Charles Grob, the UCLA psychiatrist whose 2011 pilot study of psilocybin for cancer anxiety cleared the path for the NYU and Hopkins trials, acknowledges that “in a lot of ways we are simply picking up the torch from earlier generations of researchers who had to put it down because of cultural pressures.” But if psychedelics are ever to find acceptance in modern medicine, all this buried knowledge will need to be excavated and the experiments that produced it reprised according to the prevailing scientific standards.

Yet even as psychedelic therapies are being tested by modern science, the very strangeness of these molecules and their actions upon the mind is at the same time testing whether Western medicine can deal with the implicit challenges they pose. To cite one obvious example, conventional drug trials of psychedelics are difficult if not impossible to blind: most participants can tell whether they’ve received psilocybin or a placebo, and so can their guides. Also, in testing these drugs, how can researchers hope to tease out the chemical’s effect from the critical influence of set and setting? Western science and modern drug testing depend on the ability to isolate a single variable, but it isn’t clear that the effects of a psychedelic drug can ever be isolated, whether from the context in which it is administered, the presence of the therapists involved, or the volunteer’s expectations. Any of these factors can muddy the waters of causality.

And how is Western medicine to evaluate a psychiatric drug that appears to work not by means of any strictly pharmacological effect but by administering a certain kind of experience in the minds of the people who take it?

“If psychedelic therapy proves successful, it will be because it succeeds in rejoining the brain and the mind in the practice of psychotherapy. At least that’s the promise.”

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Add to this the fact that the kind of experience these drugs sponsor often goes under the heading of “spiritual,” and you have, with psychedelic therapy, a very large pill for modern medicine to swallow. Charles Grob well appreciates the challenge but is also refreshingly unapologetic about it: he describes psychedelic therapy as a form of “applied mysticism.” This is surely an odd phrase to hear on the lips of a scientist, and to many ears it sounds dangerously unscientific.

“For me that is not a medical concept,” Franz Vollenweider, the pioneering psychedelic researcher, told Science magazine, when asked to comment on the role of mysticism in psychedelic therapy. “It’s more like an interesting shamanic concept.” But other researchers working on psychedelics don’t run from the idea that elements of shamanism might have a role to play in psychedelic therapy—as indeed it has probably done for several thousand years before there was such a thing as science. “If we are to develop optimal research designs for evaluating the therapeutic utility of hallucinogens,” Grob has written, “it will not be sufficient to adhere to strict standards of scientific methodology alone. We must also pay heed to the examples provided us by such successful applications of the shamanic paradigm.” Under that paradigm, the shaman/therapist carefully orchestrates “extrapharmacological variables” such as set and setting in order to put the “hyper-suggestible properties” of these medicines to best use. This is precisely where psychedelic therapy seems to be operating: on a frontier between spirituality and science that is as provocative as it is uncomfortable.

Yet the new research into psychedelics comes along at a time when mental health treatment in this country is so “broken”—to use the word of Tom Insel, who until 2015 was director of the National Institute of Mental Health—that the field’s willingness to entertain radical new approaches is perhaps greater than it has been in a generation. The pharmacological toolbox for treating depression—which afflicts nearly a tenth of all Americans and, worldwide, is the leading cause of disability—has little in it today, with antidepressants losing their effectiveness and the pipeline for new psychiatric drugs drying up. Pharmaceutical companies are no longer investing in the development of so-called CNS drugs—medicines targeted at the central nervous system. The mental health system reaches only a fraction of the people suffering from mental disorders, most of whom are discouraged from seeking treatment by its cost, social stigma, or ineffectiveness. There are almost 43,000 suicides every year in America (more than the number of deaths from either breast cancer or auto accidents), yet only about half of the people who take their lives have ever received mental health treatment. “Broken” does not seem too harsh a characterization of such a system.

Jeffrey Guss, a Manhattan psychiatrist and a co-investigator on the NYU trial, thinks the moment could be ripe for psychotherapy to entertain a completely new paradigm. Guss points out that for many years now “we’ve had this conflict between the biologically based treatments and psychodynamic treatments. They’ve been fighting one another for legitimacy and resources. Is mental illness a disorder of chemistry, or is it a loss of meaning in one’s life? Psychedelic therapy is the wedding of those two approaches.”

In recent years, “psychiatry has gone from being brainless to being mindless,” as one psychoanalyst has put it. If psychedelic therapy proves successful, it will be because it succeeds in rejoining the brain and the mind in the practice of psychotherapy. At least that’s the promise.

For the therapists working with people approaching the end of life, these questions are of more than academic interest. As I chatted with Stephen Ross and Tony Bossis in the NYU treatment room, I was struck by their excitement, verging on giddiness, at the results they were observing in their cancer patients—after a single guided psilocybin session. At first, Ross couldn’t believe what he was seeing: “I thought the first ten or twenty people were plants—that they must be faking it. They were saying things like ‘I understand love is the most powerful force on the planet’ or ‘I had an encounter with my cancer, this black cloud of smoke.’ People were journeying to early parts of their lives and coming back with a profound new sense of things, new priorities. People who had been palpably scared of death—they lost their fear. The fact that a drug given once could have such an effect for so long is an unprecedented finding. We have never had anything like that in the psychiatric field.”

This is when Tony Bossis first told me about his experience sitting with Patrick Mettes as he journeyed to a place in his mind that, somehow, lifted the siege of his terror.

“You’re in this room, but you’re in the presence of something large. I remember how, after two hours of silence, Patrick began to cry softly and say, twice, ‘Birth and death is a lot of work.’ It’s humbling to sit there. It’s the most rewarding day of your career.”

As a palliative care specialist, Bossis spends a lot of his time with the dying. “People don’t realize how few tools we have in psychiatry to address existential distress.” Existential distress is what psychologists call the complex of depression, anxiety, and fear common in people there is an answer, Bossis believes, it is going to be more spiritual in nature than pharmacological.

“So how do we not explore this,” he asks, “if it can recalibrate how we die?”

Michael Pollan, recently featured on Netflix in the four-part series Cooked, is the author of seven previous books, including Food Rules, In Defense of Food, The Omnivore’s Dilemma, and The Botany of Desire, all New York Times bestsellers. His most recent book is How to Change Your Mind. A longtime contributor to the New York Times Magazine, he is also the John S. and James L. Knight Professor of Journalism at Berkeley. In 2010, Time magazine named him one of the one hundred most influential people in the world.